Exosomes derived from Vδ2-T cells control Epstein-Barr virus–associated tumors and induce T cell antitumor immunity

Abstract

Treatment of life-threatening Epstein-Barr virus (EBV)–associated tumors remains a great challenge, especially for patients with relapsed or refractory disease. Here, we found that exosomes derived from phosphoantigen-expanded Vδ2-T cells (Vδ2-T-Exos) contained death-inducing ligands (FasL and TRAIL), an activating receptor for natural killer (NK) cells (NKG2D), immunostimulatory ligands (CD80 and CD86), and antigen-presenting molecules (MHC class I and II). Vδ2-T-Exos targeted and efficiently killed EBV-associated tumor cells through FasL and TRAIL pathways and promoted EBV antigen–specific CD4 and CD8 T cell expansion. Administration of Vδ2-T-Exos effectively controlled EBV-associated tumors in Rag2−/−γc−/− and humanized mice. Because expanding Vδ2-T cells and preparing autologous Vδ2-T-Exos from cancer patients ex vivo in large scale is challenging, we explored the antitumor activity of allogeneic Vδ2-T-Exos in humanized mouse cancer models. Here, we found that allogeneic Vδ2-T-Exos had more effective antitumor activity than autologous Vδ2-T-Exos in humanized mice; the allogeneic Vδ2-T-Exos increased the infiltration of T cells into tumor tissues and induced more robust CD4 and CD8 T cell–mediated antitumor immunity. Compared with exosomes derived from NK cells (NK-Exos) with direct cytotoxic antitumor activity or dendritic cells (DC-Exos) that induced T cell antitumor responses, Vδ2-T-Exos directly killed tumor cells and induced T cell–mediated antitumor response, thus resulting in more effective control of EBV-associated tumors. This study provided proof of concept for the strategy of using Vδ2-T-Exos, especially allogeneic Vδ2-T-Exos, to treat EBV-associated tumors.

MicroRNA and Other Non-Coding RNAs in Epstein–Barr Virus-Associated Cancers

“…For example, miRNA-sponges or anti-miRNA oligonucleotide therapeutic 'antagomirs' have been utilized to effectively suppress EBV-driven tumors [176,239]. A new technology is 'exosome-based therapy' with loaded immunostimulatory cargo as cell-free immunotherapy for EBV-associated malignancies [240]. The tumor-suppressive role for other miRNAs (miR-216b) through inhibition of KRAS-related AKT and ERK signaling has also been shown in NPC as a proof of concept [241].…”

Engineered neutrophil-derived exosome-like vesicles for targeted cancer therapy

“…In addition, natural killer (NK) cell–derived exosomes exert cytotoxic effects on tumor cells by delivering functional NK proteins, namely, FasL and perforin ( 5 – 8 ). Moreover, exosomes derived from γδ2-T cells contain death-inducing ligands [FasL and TRAIL (TNF related apoptosis inducing ligand)], which target and efficiently kill Epstein-Barr virus–associated tumor cells ( 9 ). Previous studies have used neutrophil-derived EVs to treat arthritis and sepsis ( 10 , 11 ).…”

New insights into Epstein‑Barr virus‑associated tumors: Exosomes (Review)

“…Therefore, targeting EBV + exosomes is considered as a promising new treatment for EBV + tumors. Wang et al ( 120 ) found that exosomes derived from phosphoantigen-expanded Vδ2-T (Vδ2-T-Exos) cells could promotes EBV antigen-specific CD4 and CD8 T cell expansion and kill EBV-associated tumor cells through FasL/TNF-related apoptosis-inducing ligand pathways. These findings suggested a strategy for the treatment of EBV-associated tumors using Vδ2-T-Exos.…”